Safety and optimal timing of staged nipple-sparing mastectomy following nipple repositioning in ptotic breasts: a systematic review protocol

Abstract

Background

In ptotic/macromastic breasts, nipple-sparing mastectomy (NSM) risks ischemic complications. Staging with nipple repositioning (mastopexy or breast reduction) may improve perfusion, but uncertainty remains regarding safety and optimal timing.

Methods

PRISMA guidelines will be followed. The database search will be conducted using MEDLINE (PubMed), Scopus, Web of Science, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.org targeting studies from inception to search date. Meta-analysis will be performed using Review Manager 5.4 software; forest plots will be used for two-arm studies to calculate pooled risk ratios, heterogeneity using I² statistics, and p-value for overall effect.

Discussion

Due to the conflicting studies regarding the optimal timing and safety of nipple-repositioning before NSM, a systematic review and meta-analysis is required to provide more definitive evidence-based recommendations regarding the optimal timing and safety of this staged approach. Limitations may include the predominance of observational studies, heterogeneity in intervals, and inconsistent reporting that may limit the certainty of our conclusions.

Systematic review registration

ROSPERO CRD42024513738

Supplementary Information

The online version contains supplementary material available at 10.1186/s13643-026-03129-6.

Introduction

Breast cancer remains the most commonly diagnosed malignancy among women worldwide, accounting for approximately 25% of all cancer cases and representing a leading cause of cancer-related mortality in women [1, 2]. The evolution of breast cancer surgery has led to a paradigm shift toward more conservative and reconstructive approaches that aim to preserve both form and function while maintaining oncologic safety [3, 4]. Nipple-sparing mastectomy (NSM) has emerged as a preferred technique in this regard, offering superior aesthetic outcomes and improved psychological well-being compared to traditional mastectomy techniques [5–8].

Nonetheless, NSM is not without its challenges, particularly in women with large or ptotic breasts. These patients face an increased risk of complications such as compromised nipple-areolar complex (NAC) vascularity, NAC necrosis, and mastectomy skin flap necrosis due to impaired blood supply [9, 10]. Thus, the safety of NSM in this patient population has been a subject of ongoing research. To mitigate these risks, a staged approach involving mastopexy or breast reduction prior to NSM has been recommended. This technique aims to improve blood supply, facilitate breast reshaping, and optimize reconstructive outcomes, thereby expanding the indications for NSM in women with large or ptotic breasts [11–15]. By reshaping the breast mound and optimizing blood supply to the NAC prior to mastectomy [16, 17], staged NSM following mastopexy or breast reduction offers the potential for reduced complication rates such as NAC necrosis. Despite the increasing popularity of this approach, there remains a need to systematically evaluate the safety, efficacy, and optimal timing of NSM following mastopexy or breast reduction [10, 11, 13, 18]. Additionally, the optimal timing between mastopexy and NSM remains a subject of debate, with some studies suggesting a waiting period of a few months [11, 19] to allow for neovascularization, while others report lower incidences of NAC and flap necrosis with intervals up to 5 years [20]. Confounding by radiotherapy, smoking, BMI, and pedicle selection further clouds interpretation, and patient-reported outcomes are seldom captured. Alternative strategies (single-stage skin-reducing NSM, immediate mastopexy/reduction with NSM, skin-sparing mastectomy with later nipple reconstruction, or free-nipple grafting) may offer shorter timelines or technical simplicity but may also trade-off higher ischemic risk, loss of nipple sensation/projection, or inferior aesthetic outcomes. Clear guidance on when staging is preferable and how long to wait remains lacking [11, 13, 18].

Prior syntheses comparing NSM vs skin-sparing approaches report favorable QOL and aesthetic outcomes for NSM but did not isolate staged mastopexy/reduction in ptotic anatomies or address inter-stage timing [7]. Contemporary single-center series suggest staging can expand candidacy yet remain limited by retrospective design, heterogeneous pedicles, and variable intervals [21]. These limitations motivate a timing-specific review. The lack of consensus and oncology guidelines (e.g., NCCN Breast Cancer Guidelines) emphasizes the need for a systematic review and meta-analysis to draw more definitive conclusions and guidelines. Therefore, this protocol aims to establish a framework for our study to evaluate the optimum time interval between mastopexy prior to performing NSM, complication rates, and oncologic safety. To our knowledge, this will be the first systematic review on safety and optimal timing of this staged approach.

Methodology

Reporting

This review has been registered with the International Prospective Register of Systematic Reviews (PROSPERO), part of the National Institute for Health Research (NIHR). Registration is as follows: PROSPERO 2024 CRD42024513738 [22], the regulations of the Preferred Reporting Items of Systematic reviews and Meta-Analyses (PRISMA) will be followed [23], and a summary of study selection will be presented in a PRISMA flow diagram as shown in Fig. 1. This protocol followed the PRISMA-P guidelines for protocols (supplementary material) as with our previously published protocols [24–28]. We will report according to PRISMA 2020, provide a populated checklist, and appraise methodological quality using AMSTAR 2 in the final manuscript.

Fig. 1.

PRISMA flow diagram that will be used to summarize study selection, screening, and number of included studies

Study question (Fig. 2)

Fig. 2.

Conceptual schematic of staged nipple-sparing mastectomy pathway. Stage 1: Nipple repositioning (mastopexy or reduction) to improve vascularity and reshape the envelope. Interval: Variable waiting period allowing tissue perfusion optimization (analyzed as a moderator). Stage 2: Nipple-sparing mastectomy with reconstruction. Abbreviations: NSM, nipple-sparing mastectomy; NAC, nipple–areolar complex; PROMs, patient-reported outcome measures

What is the efficacy, oncologic safety, and optimal timing of staged NSM following mastopexy or breast reduction in patients with large or ptotic breasts?. Figure 2 illustrates the staged pathway and highlights the inter-stage interval as the key exposure of interest.

Literature search

A systematic literature search has been conducted with the following databases: MEDLINE (PubMed), Scopus, Web of Science, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.org. The search timeframe includes all studies from inception to search date. No language or date restrictions will be applied. We combined MeSH and free-text synonyms for “nipple-sparing mastectomy,” “mastopexy,” “reduction mammaplasty,” and complications, using Boolean operators and proximity terms. Search strategy keywords included the following terms in various combinations and forms:

• • Nipple-sparing mastectomy
  • Mastopexy, breast reduction, and mammaplasty
  • Breast cancer
  • Postoperative complications, treatment outcomes, cancer recurrence, and satisfaction

The full search strategy can be found in the supplementary file. We will perform backward and forward citation chasing for all included studies: screening reference lists (backward) and “cited-by” records via Scopus/Google Scholar (forward). We will also screen related articles and trial registry entries for additional eligible studies. We will rerun all database searches within 30 days of journal submission and again prior to final acceptance. Newly eligible studies will be incorporated and the PROSPERO record updated to reflect any changes to methods or scope.

Study selection and data extraction

Studies will be screened according to PICO criteria (Table 1) and the inclusion and exclusion criteria (Table 2) by two independent reviewers. Non-randomized (retrospective and prospective) studies and randomized control trials will be included. Titles and abstracts will be screened followed by full-text screening. Information from studies that pass initial and full-text screening will be extracted by two independent reviewers, and conflicts will be resolved by a third reviewer. Data will be extracted into a spreadsheet. Outcome data will include time interval between mastopexy and NSM, partial and complete NAC necrosis, mastectomy skin flap necrosis, and other surgical complications. Outcomes on oncologic safety (e.g., cancer recurrence) will also be assessed. Demographics data will include age, body mass index, diabetes, smoking status, radiotherapy, and chemotherapy. The data-extraction form will be piloted independently by two reviewers on the first five eligible studies to ensure consistency. Discrepancies will be discussed, and the form refined a priori before full extraction. For missing, unclear, or unpublished outcome data, we will contact corresponding authors. If no response after two emails 14 days apart, we will impute only prespecified transforms (e.g., converting medians/IQR to means/SD using validated methods) and will flag such cases for sensitivity analysis.

Table 1.

PICO criteria for study selection

Population	1) Patients with breast cancer and enlarged or ptotic breasts undergoing nipple repositioning surgery (mastopexy or breast reduction) prior to therapeutic NSM 2) Patients with breast cancer and enlarged or ptotic breasts undergoing therapeutic NSM without nipple repositioning surgery
Intervention	Mastopexy or breast reduction prior to NSM
Comparison	Nonstaged NSM in breast cancer patients with ptotic breasts
Outcome	1) Complications (NAC necrosis must be present) 2) Oncologic safety 3) Time interval between mastopexy or breast reduction and NSM (must be present) 4)Secondary outcomes will include patient-reported outcomes (e.g., BREAST-Q domains such as satisfaction with breasts, psychosocial, physical, and sexual well-being) and nipple sensation (binary or ordinal scales)

Population (ptotic/macromastic breasts undergoing NSM), intervention (prior mastopexy/reduction), comparator (non-staged NSM in ptotic breasts), and outcomes (ischemic complications, oncologic safety, and inter-stage interval) defining eligibility and analytic focus. Abbreviations: NSM, nipple-sparing mastectomy; NAC, nipple–areolar complex; PROMs, patient-reported outcome measures

Table 2.

Inclusion and exclusion criteria for study selection

Inclusion criteria

Observational studies where nipple repositioning surgery was performed prior to NSM Studies reporting complication rates (NAC necrosis and mastectomy skin flap necrosis), oncologic safety, and time interval between nipple repositioning surgery and NSM

Exclusion criteria

Studies where mastopexy was performed after (instead of prior to) NSM Case reports, case series (may only be summarized descriptively), reviews, letters to the editor, commentaries, and editorials Studies with insufficient data on NAC necrosis Studies with insufficient data on time interval between nipple repositioning surgery and NSM Studies involving patients with previous breast surgery or reconstruction Studies on mastectomy techniques other than NSM

Operational criteria used for screening and eligibility, including requirements for reporting NAC necrosis and the inter-stage interval, and exclusions such as mastopexy performed after NSM, insufficient outcome reporting, and non-eligible study designs. Abbreviations: NSM, nipple-sparing mastectomy; NAC, nipple–areolar complex; PROMs, patient-reported outcome measures

Outcome harmonization and hierarchy

NAC outcomes will be abstracted using a pre-specified hierarchy to improve reproducibility across heterogeneous reporting. When multiple NAC endpoints are reported, we will prioritize the following: complete NAC necrosis, partial NAC necrosis, and composite “ischemia/epidermolysis/ischemic changes” when necrosis is not explicitly defined. If a study reports a combined endpoint (partial + complete) without separable data, it will be recorded as a composite necrosis endpoint and analyzed separately from complete necrosis where possible. When terminology is ambiguous (e.g., “epidermolysis” without necrosis), it will be coded as ischemia-related change unless the authors clearly define it as necrosis.

Unit of analysis

We will extract outcomes at the breast level when available. If only per-patient outcomes are reported, we will extract per-patient results and analyze separately or convert cautiously only when methods allow (e.g., unilateral cases clearly indicated). Discrepancies in reporting unit (breast vs patient) will be explored in sensitivity analyses.

Adjusted estimates

When available, we will preferentially extract adjusted effect estimates (e.g., adjusted odds ratios/risk ratios/hazard ratios) for comparisons involving timing or staging strategy, along with covariates used. When only crude event data is available, unadjusted estimates will be calculated and clearly labeled as such. Adjusted and unadjusted estimates will not be pooled together unless methodologically justified; otherwise, they will be synthesized separately or narratively.

Study quality

Quality assessment and risk of bias will be assessed using the Cochrane RoB 2 score for randomized control trials, and the ROBINS-I tool will be used for non-randomized studies. Studies will be independently reviewed by two authors. Any amendments to the protocol will be documented via updates on PROSPERO and reflected in the final systematic review manuscript.

Statistical analysis

Analysis will be performed on SPSS and Review Manager 5.4 software (for meta-analysis). Dichotomous data with outcomes comparing staged versus non-staged mastopexy prior to NSM will be presented as risk ratios (RR) with their respective 95% confidence intervals (CI) using the Mantel–Haenszel method. Continuous data will be presented as mean differences (MD) with their respective CI using the inverse variance method. Heterogeneity will be assessed using Q, τ², and I² statistics; in addition, prediction intervals will be included as they more accurately quantify between-setting variability and estimate the true effect a clinician can expect in their own future patients [29–31]. A random-effects model will be applied to all outcomes due to potential heterogeneity across the included studies [32, 33]. A sensitivity analysis (leave-one-out test) will be performed if heterogeneity is found to be significant (p < 0.05); further, studies at serious/critical risk of bias will be excluded. Forest plots will be created for two arm studies, including heterogeneity and p-value for overall effect. A p-value less than 0.05 will be considered significant. Subgroup analyses on different types of breast reduction (e.g., superomedial and inferior pedicles), reconstruction [34], BMI, smoking status, and radiotherapy will be performed if there is enough data. Because oncologic indication may influence timing and ischemic risk, therapeutic and prophylactic NSM cases will be abstracted separately and, where data permit, analyzed in stratified meta-analyses (therapeutic vs prophylactic). When studies report mixed indications without separable data, we will conduct sensitivity analyses excluding those cohorts. If data permits, we will perform cumulative meta-analysis by publication year for key outcomes (NAC necrosis, skin-flap necrosis) to assess temporal stabilization of effect estimates and the influence of early vs contemporary techniques. Publication bias will be assessed using funnel plots and Egger’s test where an outcome has been reported by 10 or more studies [35].

Timing as exposure

Inter-stage interval will be extracted in its most granular form (days/weeks/months). Where sufficient data are available (≥ 3 studies reporting outcomes across ≥ 3 distinct timing values), timing will additionally be modeled as a continuous exposure using meta-regression and, where feasible, dose–response approaches (e.g., restricted cubic splines) to explore nonlinear relationships. If continuous modeling is not feasible due to sparse reporting, timing will be analyzed categorically using pre-specified strata informed by biologic plausibility and common clinical practice (e.g., ≤ 8 weeks, > 8–16 weeks, > 16–24 weeks, and > 24 weeks), with strata collapsed as needed to preserve interpretability and avoid arbitrary cutpoints.

Contingency analysis plan

If meta-analysis is precluded by sparse data, incompatible effect measures, or very high heterogeneity, we will conduct a SWiM-aligned narrative synthesis using structured tabulation of study characteristics and outcomes, present ranges and medians with interquartile ranges, and, where feasible, calculate unweighted and variance-weighted summaries.

Heterogeneity thresholds and decision rules

We will interpret I² as low (25–49%), moderate (50–74%), and high (≥ 75%); τ² will be reported with prediction intervals. If I² ≥ 75% and heterogeneity is not explained through prespecified subgrouping/meta-regression, we will abstain from pooling and revert to the contingency analysis plan. We will also report between-study prediction intervals for all pooled effects.

The synthesis will prioritize clinically interpretable estimates (pooled risks with prediction intervals) and preplanned subgrouping to contextualize variability. The following section appraises the certainty of these estimates and identifies gaps that warrant prospective RCTs and standardized PROMs.

Certainty of evidence

We will assess the certainty of evidence for each critical outcome using GRADE, considering risk of bias, inconsistency, indirectness, imprecision, and publication bias. Observational evidence will start at “low” and may be rated up or down per GRADE guidance. Evidence profiles and Summary of Findings tables will be generated in GRADEpro.

Scope and interpretive intent

Because the available evidence is expected to be predominantly observational and heterogeneous, this review is intended to be hypothesis-generating rather than definitive (particularly regarding “optimal” inter-stage timing). Accordingly, the timing synthesis will focus on identifying plausible safe windows and commonly used intervals associated with acceptable complication profiles, rather than prescribing a single optimal interval.

Definitions

For this review, “nipple repositioning” refers to staged procedures intended to relocate the nipple–areolar complex to a more favorable position before NSM (e.g., mastopexy, reduction mammaplasty, or other planned repositioning maneuvers). In contrast, “surgical delay” refers to procedures intended primarily to augment NAC/skin flap vascularity prior to NSM without meaningful nipple relocation (e.g., delay incisions, undermining, devascularization maneuvers, or partial elevation designed to precondition perfusion). Studies that combine elements of both will be included if they clearly describe the intent and sequence; during synthesis, they will be categorized based on the primary intent (repositioning vs delay) and reported technique.

Oncologic outcomes

Recurrence outcomes (local, regional, distant) will be extracted along with follow-up duration and definitions used. Given expected heterogeneity and limited follow-up, oncologic outcomes will be synthesized descriptively unless a sufficient number of studies report comparable endpoints with adequate follow-up. For any quantitative synthesis, we will require clearly defined recurrence outcomes and a minimum follow-up threshold (e.g., ≥ 12 months median/mean follow-up), recognizing that longer-term recurrence risk may remain incompletely captured.

Patient-reported outcomes

PROMs (including satisfaction, psychosocial well-being, and nipple sensation when reported) will be summarized narratively due to anticipated heterogeneity in timepoints and selective reporting. Where comparable timepoints are available across multiple studies, pooling may be considered; otherwise, results will be reported with standardized directionality (improved/unchanged/worsened) relative to baseline or comparator when applicable.

Discussion

NSM in patients with macromastia or ptosis remains clinically attractive but technically fraught because nipple–areolar complex (NAC) and skin-flap ischemia are more common in this anatomy. Staging with mastopexy or breast reduction is increasingly used to reshape the envelope and improve perfusion before NSM, yet guidance on efficacy, safety, and — most importantly — how long to wait between stages is inconsistent across single-center series with heterogeneous techniques, reporting windows, and outcome definitions. These uncertainties leave surgeons and patients without evidence-based counseling on risks, timing, and reconstructive choices. This protocol lays the framework for a study that aims to address that gap by synthesizing and quantitatively analyzing the available data on staged mastopexy/reduction prior to NSM with explicit attention to timing.

The planned review is designed to yield clinically actionable estimates rather than study-specific anecdotes. We will aggregate rates of NAC necrosis (partial/complete), mastectomy skin-flap necrosis, infection, implant loss/failure, reoperation, oncologic outcomes, and (where feasible) pool effects using random-effects meta-analysis with full heterogeneity reporting; emphasis will be placed on prediction intervals to convey the range of effects a clinician might expect in a new setting and on exploring the interval between surgeries as a moderator through prespecified subgrouping and, when data permit, meta-regression. Because selection, technique, and adjuvant therapy can influence ischemic risk, we will examine clinically relevant covariates such as pedicle choice, radiotherapy exposure, smoking status, BMI, and reconstructive modality. We will standardize outcome definitions and units of analysis (per breast versus per patient), contact study authors for missing data when possible, and perform sensitivity analyses that exclude high-risk-of-bias studies or imputed statistics to assess robustness. Certainty of evidence will be graded for critical outcomes to make the strength of any recommendations transparent.

Despite its potential advantages, the optimal timing between mastopexy and NSM remains debated. Some studies suggest that a delay of 6 months allows for adequate neovascularization, reducing NAC complication rates [13], while others report similar outcomes with shorter intervals of 3 months [11, 36]. This review aims to synthesize current evidence to determine the safest and most effective timing for staged NSM. Prior reviews (e.g., Tondu 2020 [10], Clarijs 2023 [7]) summarize indications and QOL/complications across NSM strategies but do not isolate staged mastopexy/reduction in ptotic breasts or define optimal inter-stage timing. By quantifying timing as a moderator and grading certainty, our review aims to inform both individual counseling and future recommendations by societies (e.g., NCCN, ASPS) where current guidance is not timing-specific in ptosis.

Oncologic safety remains paramount. Emerging nonsurgical technologies (e.g., smart drug-delivery biosensors) are being explored in other cancers; however, they currently have no bearing on surgical selection or timing for NSM/SSM in ptotic breasts and thus were not reviewed here [37–39] but will be discussed as potential treatments in more detail in our final study.

While mastopexy or breast reduction about 11 weeks before NSM does not appear to compromise oncologic control [40], more data is needed to assess long-term recurrence and the optimum time interval to maximize survival outcomes. By addressing these gaps in the literature, this review aims to provide evidence-based recommendations for the safety, efficacy, and optimal timing of NSM following mastopexy or breast reduction. To facilitate clinical decision-making, we will categorize risk as follows: complete NAC necrosis ≤ 5% (low), 5–10% (moderate), and > 10% (high), informed by contemporary ranges of NSM necrosis rates reported in recent series and reviews. Further, where ≥ 10 studies report a given outcome, we will perform random-effects meta-regression (REML), and if enough data is reported in the included studies, a subgroup analysis will be performed for the type of breast reduction (e.g., superomedial pedicle or inferior pedicle) [41] to determine the most suitable approach with the aim of maximizing oncologic safety while minimizing risk of NAC necrosis.

We anticipate that this approach will clarify whether staging reliably lowers ischemic complications, identify a practical timing window when oncologic urgency allows, and highlight circumstances in which alternative strategies may be preferable. If the synthesis identifies reproducible reductions in ischemic complications associated with specific inter-stage intervals, these estimates could inform future NCCN/ASPS guidance for patient selection and counseling. Reporting quantitative benchmarks (e.g., prediction-interval ranges for complete NAC necrosis by interval strata) may provide a pragmatic “safe-window” reference when oncologic urgency allows staging.

Several limitations are expected. The evidence base is likely to be dominated by retrospective observational studies and small case series, with heterogeneity in patient selection, surgical techniques, reconstructive approaches, complication definitions, and follow-up duration. Reporting of timing may be inconsistent, and confounding by indication (e.g., selecting longer intervals for higher-risk patients) may limit causal inference regarding an “optimal” interval. These factors may reduce the feasibility of quantitative pooling for some outcomes and may result in lower certainty of evidence. Further, generalizability may be limited because many reports come from single-center, high-volume reconstructive practices with specialized expertise and well-developed perioperative pathways. Findings may not fully extrapolate to lower-volume centers, different healthcare systems, or resource-limited settings. In addition, evolving reconstructive techniques and perioperative protocols may reduce applicability of older studies; this reinforces the value of examining temporal trends and incorporating cumulative synthesis where feasible.

Despite these challenges, the planned review addresses an important clinical gap and may support more standardized reporting and more consistent counseling in ptotic patients considered for NSM. Future work should prioritize prospective, multicenter cohorts (or pragmatic comparative studies) with standardized definitions of complications and explicit reporting of timing, technique details, and risk modifiers (e.g., BMI, smoking, diabetes, radiation, incision pattern, and reconstruction type). Such studies are needed to move from describing common practice patterns toward establishing more robust, patient-specific timing recommendations.

Conclusion

This protocol outlines the framework for a systematic review and timing-focused synthesis evaluating staged approaches to enable NSM in patients with ptotic breasts following prior nipple repositioning procedures (e.g., mastopexy or reduction). By systematically identifying and appraising the available evidence and extracting interstage intervals alongside clinically relevant outcomes, this review aims to clarify the safety profile of staging and to characterize the timing ranges used in contemporary practice. The anticipated output is a structured summary of existing staged pathways and an evidence-informed description of commonly reported intervals that may guide surgical planning and patient counseling.

Authors’ contributions

YT designed the study with guidance from AJS. GG and SS assisted with study design. All authors read and approved the manuscript prior to submission.

Funding

The authors have not received any financial support.

Data availability

All analytic code, RevMan exports, and generated plots will be submitted as supplementary files and mirrored in the OSF repository.

Declarations

Ethics approval and consent to participate

No IRB approval is required as this review analyzes papers which are already published and in the public domain. Only published, aggregate data will be analyzed; no patient-level or identifiable data will be accessed. On completion, we will deposit the de-identified extraction spreadsheet or upload it as supplementary material with the final manuscript.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.